Neurogenesis, or the birth of new neurons, continues throughout adult life in discrete regions of the forebrain (the sub-ventricular zone and hippocampus) in mammals including humans. Adult neurogenesis contributes in a crucial way to the ability of the brain to function normally. Perturbations of this process have been implicated in affective disorders including anxiety and depression, as well as in problems related to learning and memory. Understanding the basic biology of neural stem cells and the molecular and cellular regulatory mechanisms of neurogenesis will potentially have a significant impact on repairing these disease states and promoting the maintenance of healthy brain tissues. Recently, cells with proliferative abilities and expressing neural stem cell markers have been found throughout the brain ventricular zone in zebrafish, a vertebrate genetic model organism that shares considerable similarity with mammals and is amenable to genetic/chemical screening and in vivo imaging. I am interested in investigating molecular mechanisms that regulate the specification, maintenance, and differentiation of adult neural stem cells in zebrafish, through analyzing the function of an evolutionarily conserved zinc finger-containing protein named Fezl. Fezl is expressed in forebrain embryonic progenitor cells early in development and is detected in the ventricular zone of post-embryonic and adult brains. A mutant named too few was isolated in our laboratory for its deficit in brain dopamine neurons and was later found to disrupt the fezl gene. The specific aims are as follows: 1) Test the hypothesis that Fezl demarcates the ontogeny of adult neural stem cells in the zebrafish forebrain, 2) Determine whether Fezl plays a functional role in adult neural stem cell maintenance or differentiation, and 3) Determine the contribution of Fezl-expressing adult ventricular progenitor cells to differentiated cells of the adult brain under normal conditions as well as in response to injury. Our previous studies have established that Fezl is expressed in self-renewing ventricular progenitor cells of the adult zebrafish telencephalon. To determine whether these Fezl-expressing cells are multipotent and can give rise to both neurons and glial cells, I will perform in vivo lineage tracing. To then investigate Fezl function in adult neural stem cells and neurogenesis, markers of neural stem cells and neurons will be examined in the wildtype and too few (Fezl) mutant, in conjunction with BrdU pulse-chase studies. I also propose to determine the contribution of these Fezl-expressing cells to differentiated cells of the adult telencephalon under normal conditions as well as in response to injury by performing lesion studies in conjunction with lineage tracing. PUBLIC HEALTH RELEVANCE: The proposed research will help us to better understand the mechanisms underlying neurogenesis in the adult central nervous system and may provide insights into novel treatments for affective and neurodegenerative disorders.